Abstract

OBJECTIVE—Coronary artery disease (CAD) is a leading cause of mortality and morbidity in diabetic patients; therefore, their risk stratification is a relevant issue. Because exercise tolerance is frequently impaired in these patients, pharmacological stress echocardiography (SE) has been suggested as a valuable alternative. Our aim was to evaluate the prognostic value of this technique in diabetic patients with known or suspected CAD.

RESEARCH DESIGN AND METHODS—A total of 259 consecutive diabetic patients underwent pharmacological SE (dobutamine in 108 patients and dipyridamole in 151 patients) and follow-up for 24 ± 22 months. A comparison between the prognostic value of SE and exercise electrocardiography (ECG) was made in a subgroup of 120 subjects.

Cardiovascular disease is the leading cause of death in patients with diabetes (1,2,3); in particular, coronary artery disease (CAD) is the cause of death in more than half of these patients (4). Diabetes is present in as many as 30% of patients hospitalized because of acute coronary syndromes (5) and is associated with greater mortality during the acute phase of myocardial infarction and a higher morbidity in the postinfarction period (6,7). The risk of adverse outcome is independent of the conventional risk factors for CAD (8): patients with diabetes but without other risk factors for atherosclerosis have a chance of death from CAD two to four times that of age-matched controls (4). Although revascularization procedures are associated with greater long-term mortality (9,10,11), coronary artery bypass grafting can improve survival in diabetic patients with multivessel CAD (12). Therefore, assessing risk for cardiac events in these patients is a relevant clinical issue. Scintigraphic imaging techniques have greater prognostic value than exercise electrocardiography (ECG) in diabetic patients (13), whereas prognostic studies with stress echocardiography (SE) are still lacking, despite the proven safety, feasibility, and diagnostic effectiveness of this technique (14,15).

The purpose of this study was twofold: 1) to assess the long-term prognostic value of SE in diabetic patients with known or suspected CAD and 2) to compare this prognostic value with that of exercise ECG.

RESEARCH DESIGN AND METHODS

Study population

The initial study population consisted of 328 diabetic patients consecutively evaluated for enrollment in a larger prospective study, which included 2,560 patients, focused on assessing the prognostic value of SE in the setting of known or suspected CAD. Diabetes had been diagnosed according to World Health Organization criteria (16). A total of 69 subjects were excluded due to one or more of the following reasons: 1) heart failure New York Heart Association Class III/IV (26 subjects); 2) metabolic and/or electrolytes unbalance (14 subjects); 3) significant valvular heart disease (10 subjects); and 4) prognostically relevant diseases (19 subjects). Consequently, 259 patients entered the study and underwent SE after giving informed consent. A total of 166 patients (64%) were considered also eligible for exercise ECG according to the following exclusion criteria: 1) uninterpretable resting ECG (artificial pacing in three and left bundle branch block in 23 patients) or 2) inability to exercise (peripheral vascular disease in 50 and orthopedic or neurological diseases in 17 patients). A total of 46 of the 166 eligible patients did not perform exercise ECGs: because of early discharge (<7 days) after acute coronary syndromes in 33 patients and because of organizational reasons or refusal in 13 patients. Therefore, 120 patients underwent both SE and exercise ECG, in random order and off cardioactive therapy, within 1–4 days. The study was approved by the institutional review committee. Clinical characteristics of the study population are listed in Table 1.

Stress echocardiography

Both dobutamine (n = 108) and dipyridamole (n = 151) were used as stressors. The choice was made by the examining cardiologist on the basis of his own experience, clinical issue, and the potential contraindications of each drug in the individual patient. Dobutamine was infused in 3-min stages of 5, 10, 20, 30, and 40 μg · kg–1 · min–1. Dipyridamole (0.56 mg/kg) was infused over 4 min; a second dose of 0.28 mg/kg over 2 min was added after 4 min. Both protocols included administration of atropine (≤1 mg) in case of negative response. Metoprolol and aminophylline were used as antidotes. The 12-lead ECG was continuously monitored throughout the test. Evident deterioration of wall motion pattern, ST depression ≥3 mm, ST elevation >1 mm, severe chest pain, significant arrhythmias, and decrease in blood pressure ≥30 mmHg were considered criteria to stop the test. Standard apical and parasternal views were recorded in a cine-loop quad-screen format for off-line comparison of rest and stress images. All echocardiograms were analyzed by two experienced observers. In case of disagreement, a third observer reviewed the images and a majority decision was reached. The left ventricular wall was divided into 16 segments (17) and scored using a 4-point scale: 1 = normal, 2 = hypokinetic, 3 = akinetic, 4 = dyskinetic. A wall motion score index (WMSI) was calculated by adding the numeric value assigned to each segment and dividing by the number of visualized segments. An inducible wall motion abnormality was defined as wall motion worsening in two or more segments. The test was considered positive in case of worse wall motion in dysfunctional segments or new wall motion abnormalities in normokinetic segments. Positivity occurring with administration of 0.56 mg/kg dipyridamole or ≤20 μg · kg–1 · min–1 dobutamine was defined as “low-dose” positivity. The test was considered negative if no change or development of hyperkinetic wall motion was observed.

Follow-up

Outcome was determined from patient interviews at the outpatient clinic, hospital chart reviews, and telephone interviews with the patient or his referring physician. Cardiac death and nonfatal reinfarction were target end points. Death was defined as cardiac if strictly related to proved cardiac causes (such as fatal reinfarction, acute heart failure, or malignant arrhythmias). Myocardial infarction was diagnosed on the basis of documented changes on ECG and increases in typical cardiac enzymes. All subjects undergoing revascularization were censored at the time of the procedure to avoid underestimation of the spontaneous event rate. Only the first event was used for statistical analysis.

Statistical analysis

Clinical and SE variables used for statistical analysis were age >70 years, sex, smoking, hypertension, dyslipidemia, exercise ECG not performed, known CAD (previous myocardial infarction and/or angiographically documented stenosis >70% in a major epicardial vessel or >50% in left main stream), SE positivity, rest WMSI, peak WMSI, and peak/rest WMSI variation. In patients undergoing both tests, exercise ECG positivity, product of peak rate and pressure, and maximal workload were also considered. Continuous variables were expressed as the mean ± 1 SD and compared by unpaired two-sample Student’s t test. The 95% CI was reported when appropriate. Proportions were compared using χ2 statistics. The individual effect of variables on event-free survival was evaluated by Cox’s proportional hazard model according to a stepwise forward procedure (18). At each step, a significance of 0.1 was required to enter into the model. The χ2 value was calculated from the log likelihood ratio. A statistically significant increase in global χ2 of the model after the addition of further variables was considered to indicate incremental prognostic value.

Cumulative survival curves as a function of time were generated with the Kaplan-Meier method and compared by the log-rank test. The statistical significance was settled at a P value <0.05. SPSS statistical software (version 7.5.1 for Microsoft Windows; SPSS, Chicago, IL) was used.

Outcome prediction

A total of 17 of 26 patients (65%) who experienced follow-up events and 91 of 233 patients (39%) who did not experience events had positive SE; conversely, the test was negative in 9 patients (35%) who experienced follow-up events and 142 patients (61%) who did not experience events (odds ratio 2.9, 95% CI 1.3–6.9, P < 0.01). Results of univariate analysis in all patients and in those undergoing both tests are listed in Table 2 and Table 3, respectively. However, Cox’s model selected peak WMSI as the only significant and independent prognostic indicator (odds ratio 11, 95% CI 4–29, P < 0.0001). Survival analysis showed positive SE to be associated with a significantly lower event-free survival as compared with negative SE. Negative exercise ECG also predicted a good prognosis, but no significant difference was found as compared with positive exercise ECG (Fig. 1).

Incremental prognostic value of SE

A total of 53 of 120 patients undergoing both tests had positive exercise ECG, whereas 50 had positive SE. Tests were both positive in 35 patients and both negative in 52 patients (agreement 72.5%, κ value 0.44, 95% CI 027–0.60). Of 10 cardiac events in this group, 6 events (2 deaths and 4 infarctions) occurred in patients with positive exercise ECG, and 8 events (4 deaths and 4 infarctions) occurred in those with positive SE.

The global χ2 of the statistical model increased from 7 to 16 (P < 0.01) when exercise ECG result was added to clinical variables. However, SE provided additional prognostic information (χ2 = 23) after adjustment for the most predictive clinical (P < 0.001) and exercise ECG variables (P < 0.01).

CONCLUSIONS

This is, to the best of our knowledge, the first study to demonstrate the prognostic value of SE in a large sample of diabetic patients with known or suspected CAD. Only one previous retrospective analysis (19) in 53 patients with type 1 diabetes undergoing dobutamine SE before kidney and/or pancreatic transplantation showed a 54% cardiac event rate among patients with abnormal SE and a 6% rate among those with normal SE during a follow-up of 418 ± 269 days.

The clinical model of the present study confirms the concept that the known CAD is independently associated with unfavorable outcome in the diabetic population and is consistent with the pivotal role of the disease as both promoter of atherogenesis (20) and prognostic determinant of cardiac morbidity and mortality (1,2,3).

In this study, 36% of the patients were ineligible for exercise ECG, and a limited functional capacity was the cause of ineligibility in 26% of these patients. Although exercise ECG is the most common stress modality used for the noninvasive evaluation of CAD, exercise tolerance in diabetic patients may be impaired, particularly because of the higher prevalence of peripheral vascular disease. In the study by Elhendy et al. (14), 13% of 1,446 consecutive patients with limited exercise capacity referred for evaluation of myocardial ischemia had an established diagnosis of diabetes. This emphasizes the central role of imaging techniques coupled with pharmacological stress for the diagnostic and prognostic assessment of CAD in these patients. Scintigraphic techniques showed a superior prognostic value compared with exercise ECG alone in diabetes (13,21,22), and the American Diabetes Association currently recommends that patients at high risk for CAD or with known CAD should undergo myocardial perfusion imaging in conjunction with treadmill or pharmacological testing (23). In particular, Kang et al. (24) recently reported that exercise and adenosine dual-isotope myocardial perfusion single photon emission tomography added incremental prognostic value over clinical information for patients with diabetes; moreover, patients with normal results on scanning had a good prognosis, similar to patients without diabetes. However, their results were based on a population referred for nuclear testing and may not be applicable to a broader population. The results of our study confirm, with a different imaging technique, the findings in nuclear studies. In particular, SE showed an excellent negative predictive value and proved to convey additional prognostic information over clinical and exercise ECG.

The follow-up period was longer in patients undergoing dipyridamole testing because this protocol was more popular at the beginning of the study. However, the indications for dobutamine stress were much more frequent in patients with known CAD and, in particular, in those with history of myocardial infarction, as mirrored by the significantly higher resting WMSI in the dobutamine group. This aspect, rather than the intrinsic prognostic value of the two protocols, may account for the borderline significance of dobutamine stress at univariate analysis.

Diabetic patients represent a population at increased risk of morbidity and mortality for CAD. Angiographic studies showed CAD to spread wider, to extend more distally, and to be associated with extensive endothelial dysfunction in these patients (25). Diabetic patients presenting with acute myocardial infarction are at increased risk of developing heart failure or of death due to the event (26,27) and benefit less from thrombolytic therapy (28). On the other hand, these patients are more likely to be without chest pain in the setting of acute coronary syndromes and are less likely to experience exertional angina with exercise testing, thus increasing the difficulty of diagnosing significant CAD. Therefore, their risk stratification is a major challenge for the cardiologist to prevent subsequent coronary events. Patients at substantial risk for CAD, such as those with multiple risk factors, abnormal resting ECG, peripheral vascular disease, proteinuria, or nephropathy, should undergo cardiac stress testing. Similarly, all diabetic patients with typical chest pain or possible anginal equivalents, such as dyspnea on exertion, should be stress tested. Furthermore, diabetic patients with known CAD should undergo stress testing to evaluate their risk and to select the best therapeutic strategy. As in nondiabetic subjects, maximal negative exercise ECG can predict a good prognosis and can be performed for screening purposes in those patients with normal resting ECG, who are likely to exercise sufficiently to reach 85% of their maximal heart rate. Patients with poor exercise tolerance but a negative result by standard ECG criteria should be considered for a different method of stress testing to improve the prognostic accuracy. The results of the present study suggest pharmacological SE as a feasible and effective alternative.

Study limitations

Some limitations of the present study must be acknowledged. First, because the study was not specifically designed for diabetic patients, some clinical variables related to the disease, particularly diabetic nephropathy and microalbuminuria, which have been indicated as independent risk factors for cardiovascular morbidity and mortality (29,30), are missing. Moreover, patients with type 1 and type 2 diabetes were not analyzed separately. However, these patients are also grouped together in the most recent recommendations (4) on diagnosis and risk stratification of CAD in people with diabetes, because they have not been analyzed separately in existing trials.

Pooled results of dipyridamole and dobutamine SE are presented. Although the two drugs can induce ischemia by different physiological mechanisms, their prognostic accuracy was shown to be comparable in multicenter studies (31). In particular, the extension and severity of induced left ventricular dysfunction were the most important predictors of cardiac events with both dipyridamole and dobutamine stress. It is logical, therefore, to expect no significant bias by the combined analysis applied in this study.

Finally, information on medical therapy was not consecutively available in this study; therefore, its influence on prognosis could not be assessed.